Genetic, post-mortem and psychopharmacologic findings support the hypothesis that hypofunction of NMDA[unreadable] receptors may contribute symptomatic manifestations of schizophrenia. One potential mechanism is through[unreadable] the glycine modulatory site on the NMDA receptor, which must be occupied by glycine/D-serine, for the[unreadable] NMDA receptor to function. The association of the risk for schizophrenia with the gene encoding G72, a[unreadable] protein that activates D-amino acid oxidase that degrades D-serine, suggests low D-serine, which has been[unreadable] reported in schizophrenia, could be one cause of NMDA receptor hypofunction. To understand better the[unreadable] role of D-serine in hippocampal physiology and behavior, we will pursue two strategies. First, we will use our[unreadable] mice with floxed serine racemase gene to suppress its expression at 4 weeks pot-partum and characterize[unreadable] the neurophysiologic and behavioral consequences. Secondly, we will characterize the effects of transfected[unreadable] G72 on D-amino acid oxidase activity and D-serine levels in vitro, in tissue culture and in vivo using[unreadable] transgenic techniques. Finally, N-acetyl aspartyl glutamate (NAAG) is catabolized by glutamate[unreadable] Carboxypeptidase II (GCPII). NAAG is a selective agonist at mGluR3 (GRM3), whose gene has been[unreadable] associated with risk for schizophrenia; and GCPII expression is reduced in schizophrenia. We will use our[unreadable] mice with floxed GCPII to suppress its expression at 4 weeks post-partum and characterize the[unreadable] neurophysiologic and behavioral consequences. We believe that these experiments should provide[unreadable] informative mutant mice that should share homologies in behavior and synaptic chemistry to schizophrenia[unreadable] and will permit correlating cognitive deficits defined by the same tasks in patients and mice to hippocampal[unreadable] electrophysiology.